Apparatus For Facilitating Transdermal Delivery Of Therapeutic Substances And Method Of Transdermally Delivering Therapeutic Substances

ABSTRACT

An apparatus ( 40 ) is disclosed for facilitating transdermal delivery of therapeutic substances. The apparatus ( 40 ) comprises means ( 44 ) for producing an electromagnetic field, control means ( 26, 34 ) arranged to control said field producing means to alternately produce active and substantially inactive electromagnetic field portions. Each active electromagnetic field portion includes an electromagnetic field packet having a plurality of successive electromagnetic field pulses, and each substantially inactive electromagnetic field portion includes no electromagnetic field pulses. During use, when the electromagnetic field is incident on a patient, dermal permeability is increased. A corresponding method is also disclosed.

FIELD OF THE INVENTION

The present invention relates to an apparatus for facilitatingtransdermal delivery of therapeutic substances and to a method oftransdermally delivering therapeutic substances.

BACKGROUND OF THE INVENTION

The use of therapeutic substances to treat and/or prevent disease,injury or disability is a cornerstone of modern human and animal relatedmedicine.

In order for such therapeutic substances to have useful effect to adesired treatment area, the substances must be physically and/orchemically available to the treatment area, and must be available in asufficient concentration to exert a beneficial biological effect.

As an alternative to conventional methods of delivery of therapeuticsubstances, transdermal delivery techniques have been developed so thata degree of site specificity is obtained and a desired concentration oftherapeutic substance is achieved which is unaltered by digestion orblood chemistry. Transdermal delivery techniques also offer thepossibility of high user compliance, ease of management, low toxicityand high cost effectiveness.

However, mammalian skin poses a significant barrier to entry for manytherapeutic substances because the lipid bilayer of the stratum corneumskin layer generally only allows very small neutrally charged particlesof the order of 1 nm to pass through. As such, transdermal delivery ofmany ions, drugs, macro molecules, DNA fragments, genes and therapeuticsubstances is problematic.

In one transdermal technique referred to as iontophoresis, an electricalenergy gradient is used to charge a target molecule and an electricalvoltage is employed to accelerate the charged target molecule towards acell membrane adjacent the target area, the energy of the targetmolecule being sufficient to cause the target molecule to pass throughthe cell membrane.

However, due to the relatively high energy levels employed, significantresidual cellular damage occurs to the skin which can manifest aslocalised burns, skin irritation and cellular fatigue. In addition,critical ionic structures of the target molecule can be inadvertentlychanged by the process.

A further transdermal delivery technique is referred to aselectroporation. With this technique, successive pulses of 1 ms to 10 msduration of the order of 100 to 200 volts are directly applied to atarget skin area using probes.

However, as with the iontophoresis technique, since relatively highenergy levels are used, significant cellular damage occurs. In addition,in view of the high voltages employed, electroporation is unsuitable touse in vivo and to date has been used only in vitro.

The barrier effect of the stratum corneum arises as a result of theintercellular lipid matrix which comprises long chain ceramides, freefatty acids, cholesterol and other lipids. The lipids are arranged intobilayers having hydrocarbon chains aligned to form an oily bilayer coreand electrically charged or polar outwardly facing head groups. Thisproduces a highly selective filter-like structure. In contrast tophospholipid bilayer membranes found elsewhere in the body, thecomposition of the stratum corneum lipid bilayers is a much more rigidand ordered structure. As a consequence, the barrier to penetration ofthe stratum corneum by therapeutic substances is much greater comparedto the corresponding barriers to penetration produced by other bodymembranes.

Therapeutic substance delivery techniques such as iontophoresis andelectroporation rely on introducing sufficient energy to the stratumcorneum to break up the inherent structure of the lipid bilayer, whichdisrupts the hydrophilic-hydrophobic orientation of the bilayer andcreates regions of random orientation through which some substances maybe introduced. Disruption of the dermal barrier effect in this way isunpredictable and provides little control over the rate of drugdelivery.

In the claims of this application and in the description of theinvention, except where the context requires otherwise due to expresslanguage or necessary implication, the words “comprise” or variationssuch as “comprises” or “comprising” are used in an inclusive sense, i.e.to specify the presence of the stated features but not to preclude thepresence or addition of further features in various embodiments of theinvention.

SUMMARY OF THE INVENTION

In accordance with an aspect of the present invention, there is providedan apparatus for facilitating transdermal delivery of therapeuticsubstances, said apparatus comprising:

means for producing an electromagnetic field;

control means arranged to control said field producing means toalternately produce active and substantially inactive electromagneticfield portions, each said active electromagnetic field portion includingan electromagnetic field packet having a plurality of successiveelectromagnetic field pulses, and each said substantially inactiveelectromagnetic field portion including no electromagnetic field pulses;

wherein during use when the electromagnetic field is incident on apatient, dermal permeability is increased.

In one arrangement, the means for producing an electromagnetic fieldincludes a coil. The means for producing an electromagnetic field mayfurther include a solid state switching device which may be a transistorsuch as a bipolar transistor connected in series with the coil.

In one arrangement, the control means is arranged to produce anenergisation signal useable to control switching of the solid stateswitching device, the energisation signal including a repeatingenergisation signal packet, each energisation signal packet including aplurality of energisation signal pulses of generally rectangularconfiguration.

The control means may comprise a microcontroller which may beprogrammable by a user. The microcontroller may be programmed such thatdermal permeability is increased at one or more specific times,permeability is increased for a specific period of time, and so on.

In one embodiment, the energisation signal packet repeats at a frequencyof between 1 Hz and 100 Hz, more particularly between 10 Hz and 50 Hz.

In one arrangement, each energisation signal packet includes between 12and 20 energisation signal pulses.

In one arrangement, the duration of each energisation signal pulse isbetween 1 μs and 1 s, more particularly between 25 μs and 100 ms.

The apparatus may take the form of a generally flat member having themeans for producing an electromagnetic field and the control meansembedded therein.

In one arrangement, the therapeutic substance is disposed on a surfaceof the apparatus. The therapeutic substance may be a drug, vaccine, ion,macromolecule, DNA fragment, gene or any other substance desired to bepassed through the skin of a patient for the purpose of obtaining abeneficial effect.

In accordance with an alternative aspect of the present invention, thereis provided a method of transdermally delivering therapeutic substances,said method comprising:

producing an electromagnetic field;

directing the electromagnetic field at a desired treatment area of apatient's skin; and

controlling the electromagnetic field so as to alternately produceactive and substantially inactive electromagnetic field portions, eachsaid active electromagnetic field portion including an electromagneticfield packet having a plurality of successive electromagnetic fieldpulses, and each said substantially inactive electromagnetic fieldportion including no electromagnetic field pulses.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be described, by way of example only,with reference to the accompanying drawings, in which:

FIG. 1 is a diagrammatic perspective view of a portion of a stratumcorneum prior to application of an electromagnetic field produced inaccordance with an apparatus and method according to the presentinvention;

FIG. 2 is a diagrammatic perspective view of the stratum corneum shownin FIG. 1 during application of an electromagnetic field produced by anapparatus and method in accordance with an embodiment of the presentinvention;

FIG. 3 is a schematic diagram of an energisation signal used to effectenergisation of an electromagnetic field generation device of anapparatus in accordance with an embodiment of the present invention;

FIG. 4 is an enlarged schematic diagram of an energisation signal packetof the energisation signal shown in FIG. 3;

FIG. 5 is a schematic diagram illustrating circuitry of an apparatus forfacilitating transdermal delivery of therapeutic substances inaccordance with an embodiment of the present invention; and

FIG. 6 is a diagrammatic perspective view of an apparatus forfacilitating transdermal delivery of therapeutic substances inaccordance with an embodiment of the present invention, the apparatusincluding the circuitry shown in FIG. 5.

DESCRIPTION OF AN EMBODIMENT OF THE INVENTION

Referring to the drawings, in FIG. 1 a portion of a stratum corneumlipid bilayer structure 10 is shown diagrammatically, the lipid bilayerstructure 10 having an oily core portion 12 formed of alignedhydrocarbon chains, and charged head portions 14.

During normal conditions, the bilayer structure 10 serves to preventparticles having a size greater than approximately 1 nm from passingthrough.

The inventor of the present invention has discovered that by applying arelatively low power electromagnetic field of particular pattern to thestratum corneum, it is possible to cause at least some of the lipids tocompact in such a way as to create a void or a region of low lipidpopulation in the stratum corneum through which therapeutic substancesmay pass. In the present example, the electromagnetic field ofpredetermined pattern causes a void 16 or region of low lipid populationwhich may be annular to be defined in the stratum corneum as showndiagrammatically in FIG. 2, the annular void 16 being temporarilypresent during and after application of the electromagnetic field, andthe structure of the stratum corneum reverting back to the barrierstructure shown in FIG. 1 at a period of time after cessation of theelectromagnetic field.

The inventor of the present invention has discovered that by applying anenergisation signal 18 of the general pattern shown in FIG. 3 to controlcircuitry of an electromagnetic field generation device such as a coil,the desired effect of creating a temporary aperture in the stratumcorneum is achieved. The energisation signal 18 has a general patternwhich comprises alternating active and inactive signal portions, theactive signal portions containing a plurality of voltage pulses and theinactive signal portions containing no voltage pulses.

In particular, the energisation signal 18 may include an active signalportion in the form of an energisation signal packet 20 which repeats ata frequency of between 1 Hz and 100 Hz, more particularly between 10 Hzand 50 Hz, with each energisation signal packet including between 12 and20 successive energisation signal pulses 22, and each successive pair ofenergisation signal packets 20 being separated by an inactive signalportion 21. The energisation pulses 22 are shown more particularly in anenlarged view of the energisation signal packet 20 shown in FIG. 4. Theduration of each energisation pulse 22 may be of the order of 1 μs to 1s, more particularly 25 μs to 100 ms.

In the present example, the time duration of the inactive portion 21,that is the time between successive active portions 20, is greater thanthe time duration of an active portion 20.

In the present example, the duration of each energisation signal pulse22 is approximately 360 μs, the duty cycle of each of the energisationsignal pulses 22 is approximately 50%, and the time duration of eachinactive signal portion 21 is 15 times greater than the time duration ofeach active signal portion 20, although it will be understood that othervariations are possible. Each energisation signal pulse 22 in thepresent example is of generally rectangular shape.

It will be understood that by applying energisation signal pulses 22 ofgenerally rectangular shape to control circuitry of an electromagneticfield generation device such as a coil, active electromagnetic fieldportions separated by inactive electromagnetic field portions areproduced, with each active electromagnetic field portion containingpackets of electromagnetic field pulses produced at a spacing determinedby the duration of an inactive electromagnetic field portion, and eachinactive electromagnetic field portion containing no electromagneticfield pulses. In the present example, the electromagnetic field strengthof the electromagnetic field signal is of the order of 3 Gauss or less.

Without wishing to be bound by theory, it is believed that permeabilityof the stratum corneum is enhanced by application of an electromagneticsignal of the type produced when an energisation signal of the generalpattern shown in FIG. 3 is applied to control circuitry of anelectromagnetic field generation device, because the plurality ofelectromagnetic pulses in the active field portion cause charging ofportions of the bilayer structure and thereby creation of a potentialdifference in the structure, and the inactive field portions cause theaccumulated charge to dissipate across the lipid bilayer. This causesportions of the bilayer structure to repel each other and thereby forman opening in the stratum corneum through which therapeutic substancesmay pass. In other words, it is believed that the electromagnetic fielddoes not in itself have any biological effect on the stratum corneum,rather the electromagnetic field induces an electrical or ionic effectin the stratum corneum which causes gaps to occur in the stratumcorneum. In view of this, it is believed that the amount of chargegenerated in the bilayer structure and thereby the degree ofpermeability is dependent in particular on the number of pulse edges ofthe energisation signal per unit time, the total number of pulse edges,and the packet frequency.

The inventor of the present invention has also discovered that thepresent transdermal delivery technique makes it possible to accuratelytarget within 3 dimensions a desired treatment area by locating theelectromagnetic field generation device (in this example a coil) abovethe desired treatment area, and modifying the packet frequency so as toinfluence the stratum corneum bilayers with little or no detectableeffect in surrounding tissue.

Referring to FIG. 5, circuitry 24 is shown for effecting generation ofan electromagnetic signal having a pattern suitable for causing anaperture to be produced in a stratum corneum.

The circuitry 24 includes a solid state switching device, in thisexample in the form of a bipolar transistor 26 connected in series withan electromagnetic field generation device, in this example in the formof a coil 28. Switching of the transistor 26 and thereby energisation ofthe coil 28 is controlled using control circuitry, in this example inthe form of a microcontroller 34 preprogrammed to generate a biasingsignal on the base of the transistor 26 corresponding in general patternto the energisation signal 18 shown in FIG. 3. However, it will beunderstood that other arrangements for effecting controlled switching ofthe transistor 26 are envisaged.

In this example, a voltage regulator 36 is also provided to produce aregulated voltage necessary for the microcontroller 34, although it willbe understood that for microcontrollers or other control circuitry whichdo not require a regulated voltage supply, the regulator 36 may beomitted.

As shown in FIG. 6, an apparatus 40 for facilitating transdermaldelivery of therapeutic substances may take the form of a generally flatrectangular member which for example may be formed of plastics material.The apparatus 40 includes a body portion 42 having embedded circuitry 24and an energy storage device such as a battery 44 for supplying power tothe circuitry 24. However, it will be understood that other types ofapparatus may be used, and that the apparatus may be mains powered.

During use, the apparatus 40 may be placed adjacent a portion of theskin through which it is desired to introduce therapeutic substances andthe circuitry 24 activated so as to cause opening of an aperture in thestratum corneum adjacent the apparatus 40.

The therapeutic substance may be disposed on a surface 46 of the bodyportion 42, may be applied directly to the skin, or may be introduced onto the skin in any other suitable way.

In an experimental example, penetration of caffeine through excisedhuman epidermal membranes was investigated using Franz-type diffusioncells and standard procedures. An electromagnetic field pattern wascreated and the penetration results compared with passive diffusion. Theelectromagnetic field pattern used was generated by applying anenergisation signal having 12 pulses at a repeating frequency of 10 Hzto a coil Each of the pulses has a duration of approximately 360 μs. Aphosphate buffered saline receptor solution was used and the amount ofcaffeine in the receptor solution determined by HPLC with UV detectionat regular time intervals up to 6 hours post application of theelectromagnetic field. In this example, the electromagnetic fieldpattern was applied for approximately 30 minutes.

It was observed that the caffeine flux associated with passive diffusionwas of the order of 4.1 μg cm⁻²h⁻¹. It was also observed that thecaffeine flux associated with the electromagnetic field patterns of thepresent invention were significantly higher than the correspondingcaffeine flux associated with passive diffusion, with the highestcaffeine flux achieved being 19.24 μg cm⁻²h⁻¹.

Similar experiments were carried out with electromagnetic fieldsgenerated by applying an energisation signal having 15 pulses of 360 μsduration at a repeating frequency of 20 Hz to a coil, and by applying anenergisation signal having 255 pulses at a repeating frequency of 2 Hzto a coil. These experiments yielded caffeine flux values of 7.20 μgcm⁻²h⁻¹ and 8.51 μg cm⁻²h⁻¹, although the latter of these experimentsproduced an effect only after 60 minutes.

A further experiment was carried out by applying an energisation signalhaving a single quasi-rectangular pulse repeated at 72 Hz to a coil.This yielded no discernable change in permeability of the stratumcorneum.

It will be appreciated that although the present embodiment is describedin relation to common rail mode generation of an electromagnetic signal,other arrangements are possible, such as biphasic mode generation of anelectromagnetic signal.

It will be appreciated that the amount of energy required to carry outthe present transdermal delivery technique is approximately 1000 timesless than the corresponding energy levels required for iontophoresis andelectroporation transdermal delivery techniques. As a consequence, thepresent technique is ideally suited to implementation in compact,portable and disposable applications, in particular for outpatient andhomecare use.

It will also be appreciated that since the present technique isinductive, the technique can operate through most non-conductivematerials such as bandages without the requirement for physical contactwith the skin.

It will also be appreciated that the present technique can not be sensedor felt by humans and, as a result, the technique is painless and hasnone of the undesirable side effects commonly associated with techniquessuch as iontophoresis and electroporation.

It will also be appreciated that the control circuitry, for example amicrocontroller, may be configured so that the apparatus carries out aspecific treatment plan, for example by generating an appropriateenergisation signal pattern and using the energisation signal to applyone or more specific electromagnetic field patterns to a target area ofa patient at specific times of for a specific time duration.

It will also be appreciated that the therapeutic substance may be adrug, vaccine, ion, macromolecule, DNA fragment, gene or any othersubstance desired to be passed through the skin of a patient for thepurpose of obtaining a beneficial effect.

Modifications and variations as would be apparent to a skilled addresseeare deemed to be within the scope of the present invention.

1. An apparatus for facilitating transdermal delivery of therapeuticsubstances, said apparatus comprising: an electromagnetic fieldgenerative device; a control device arranged to control said fieldgenerating device to alternately produce active and substantiallyinactive electromagnetic field portions, each said activeelectromagnetic field portion including an electromagnetic field packethaving a plurality of successive electromagnetic field pulses, each saidsubstantially inactive electromagnetic field portion including noelectromagnetic field pulses, and the time between successiveelectromagnetic field packets being greater than the time betweensuccessive electromagnetic field pulses.
 2. Apparatus as claimed inclaim 1, wherein the electromagnetic field generating device comprises asolid state switching device.
 3. Apparatus as claimed in claim 2,wherein the control device is arranged to produce an energisation signaluseable to control switching of the solid state switching device, eachenergisation signal packet including an active energisation signalportion including a plurality of energisation signal pulses and asubstantially inactive energisation signal portion including no signalpulses.
 4. Apparatus as claimed in claim 3, wherein at least some of thesignal pulses are of generally rectangular configuration.
 5. Apparatusas claimed in claim 1, wherein the electromagnetic field generatingdevice includes a coil.
 6. Apparatus as claimed in claim 2, wherein thesolid state switching device comprises a transistor.
 7. Apparatus asclaimed in claim 1, wherein the control device comprises amicrocontroller.
 8. Apparatus as claimed in claim 7, wherein themicrocontroller is programmable by a user so that an electromagneticsignal corresponding to a predetermined therapeutic substance deliveryplan is produced.
 9. Apparatus as claimed in claim 8, wherein themicrocontroller is programmed such that dermal permeability is increasedat one or more specific times.
 10. Apparatus as claimed in claim 8,wherein the microcontroller is programmed such that dermal permeabilityis increased for a specific period of time.
 11. Apparatus as claimed inclaim 3, wherein the energisation signal packet repeats at a frequencyof between 1 Hz and 100 Hz.
 12. Apparatus as claimed in claim 11,wherein the energisation signal packet repeats at a frequency of between10 Hz and 50 Hz.
 13. Apparatus as claimed in claim 3, wherein eachenergisation signal packet includes between 12 and 20 energisationsignal pulses.
 14. Apparatus as claimed in claim 1, wherein the durationof each energisation pulse is between 1 μs and 1 s.
 15. Apparatus asclaimed in claim 11, wherein the duration of each energisation pulse isbetween 25 μs and 100 ms.
 16. Apparatus as claimed in claim 1, whereinthe apparatus comprises a substantially flat member having theelectromagnetic field generating device and the control device embeddedtherein.
 17. Apparatus as claimed in claim 1, wherein the therapeuticsubstance is disposed on an outwardly facing surface of the apparatus.18. Apparatus as claimed in claim 1, wherein the therapeutic substanceis a drug, vaccine, ion, macromolecule, DNA fragment or gene.
 19. Amethod of transdermally delivering therapeutic substances, said methodcomprising: producing an electromagnetic field; directing theelectromagnetic field at a desired treatment area of a patient's skin;and controlling the electromagnetic field so as to alternately produceactive and substantially inactive electromagnetic field portions, eachsaid active electromagnetic field portion including an electromagneticfield packet having a plurality of successive electromagnetic fieldpulses, each said substantially inactive electromagnetic field portionincluding no electromagnetic field pulses, and the time betweensuccessive electromagnetic field packets being greater than the timebetween successive electromagnetic field pulses.
 20. A method as claimedin claim 19, wherein the step of controlling the electromagnetic fieldcomprises producing an energisation signal useable to control switchingof a solid state switching device, each energisation signal packetincluding an active energisation signal portion including a plurality ofenergisation signal pulses and a substantially inactive energisationsignal portion including no signal pulses.
 21. A method as claimed inclaim 20, wherein at least some of the signal pulses are of generallyrectangular configuration.
 22. A method as claimed in claim 19, whereinthe step of producing an electromagnetic field comprises energizing acoil.
 23. A method as claimed in claim 20, wherein the solid stateswitching device comprises a transistor.
 24. A method as claimed inclaim 19, wherein the control means comprises a microcontroller.
 25. Amethod as claimed in claim 24, further comprising the step ofprogramming the microcontroller so that during use an electromagneticsignal corresponding to a predetermined therapeutic substance deliveryplan is produced.
 26. A method as claimed in claim 25, furthercomprising the step of programming the microcontroller such that dermalpermeability is increased at one or more specific times.
 27. A method asclaimed in claim 25, further comprising the step of programming themicrocontroller such that dermal permeability is increased for aspecific period of time.
 28. A method as claimed in claim 20, whereinthe energisation signal packet repeats at a frequency of between 1 Hzand 100 Hz.
 29. A method as claimed in claim 28, wherein theenergisation signal packet repeats at a frequency of between 10 Hz and50 Hz.
 30. A method as claimed in claim 20, wherein each energisationsignal packet includes between 12 and 20 energisation signal pulses. 31.A method as claimed in claim 20, wherein the duration of eachenergisation pulse is between 1 μs and 1 s.
 32. A method as claimed inclaim 31, wherein the duration of each energisation pulse is between 25μs and 100 ms.
 33. A method as claimed in claim 19, wherein thetherapeutic substance is a drug, vaccine, ion, macromolecule, DNAfragment or gene.